Method for making a pharmaceutical formulation

ABSTRACT

The invention concerns a method for preparing a physically stable and homogeneous powdered preparation containing particles of an active agent. The particles are suspended in a suspending agent in which the particles are insoluble, and the suspending agent is evaporated from the suspension. Physiologically acceptable additives such as a carrier may optionally be added to the suspension.

This application is the U.S. National Phase under 35 U.S.C. §371 ofInternational Application PCT/F198/01001, filed Dec. 21, 1998, whichclaims priority of Finnish Patent Application No. 974664, filed Dec. 21,1997.

This invention concerns a method for preparing a physically stable andhomogenous powdered preparation containing in particulated form anactive agent and optionally conventional physiologically acceptableadditives, such as a carrier.

Powder inhalers are widely used for ozone-saving dosing of active drugsinto the lungs. These devices can be divided in two categories:

1. Devices provided with a powder reservoir and means for metering adose from the reservoir for each delivery to the patient

2. Devices provided with pre-metered powder doses in capsules, blistersetc.

The performance of any powder inhaler must fulfill the requirements ofPharmacopeias for delivered dose uniformity (±25% of mean). Also themass of respirable particles per dose and general stability of theformulation must be documented and accepted by the authorities.

Concerning inhalation, the respirable particles are commonly accepted tobe particles having an aerodynamic diameter less than 6 microns, whichcan be tested in a laboratory.

Dry powders for inhalation are normally manufactured of micron size drugparticles and a coarser carrier, e.g. lactose or glucose, by mixing themin a dry homogenizer. All micron size particles are very cohesive andtend to adhere strongly to each other and other surfaces (carrier,container, and the like). Therefore, special care must be paid in themixing process in order to obtain a homogenous blend. A non-homogenousblend will cause variations in the delivered dose, especially withreservoir devices, which additionally show a natural variation inaccuracy of metering the dose.

When a dose is inhaled a part of the micron sized drug particles isseparated from the carrier. Only particles this small deposit in thelung. If the forces adhering the drug particles onto other drugparticles or carrier particles is increased, the amount of respirableparticles will decrease and the clinical effect will be different.Altered adhesion also affects dose metering accuracy in reservoirdevices.

A common reason for agglomeration of an inhalation powder is that somesubstances, often the drug, are in an unstable state. Such instabilityis mainly caused by polymorphic crystals or amorphous matter, which tendto recrystalize in a thermodynamically most stable state.Simultaneously, micron size particles tend to fuse together and adhereon any available surfaces. Such changes take place slowly at normal roomtemperatures but are commonly accelerated by elevated temperature,presence of moisture or organic vapours.

Polymorphic crystals may form during crystallization but a proper choiceof solvent may prevent it. Amorphous material is normally formed duringhigh-energy treatment of organic solids, e.g. micronization in ajet-mill or ball-mill, or in rapid precipitation with anti-solvent orduring spray-drying. Carrier substances may contain amorphous matter aswell.

As a summary, a manufacturing method resulting in excellent homogeneityof physically stable substances is well established.

The presence and characteristics of amorphous matter in micronized drugparticles has been shown in several publications (e.g. with salbutamolby Ward and Schulz in Pharmaceutical Research, Vol. 12, No 5, 1995).

In WO 95/05805 a micronized drug or a mixture containing a micronizeddrug is stabilized by using water vapour preferably at 10-50° C. andover 75% relative humidity. This method is useful for water solublesubstances. If the mixture contains water insoluble substances, vapourtreatment with organic solvents should be carried out, too.Stabilization of dry powder is using vapour and no wet suspension ismentioned. The authors suppose that, as a rule, water soluble substancesmust be treated with water vapour and water insoluble substances withorganic vapour.

In PCT/SE92/00186 a micronized water soluble drug is stabilized in asimilar manner with ethanol, acetone or other organic vapours. Prior tothe treatment all water was removed from the drug at elevatedtemperature and under vacuum. After the treatment residues of organicsolvent were removed from the drug with an inert gas. No suspensiontreatment is mentioned.

There are some drawbacks in treating dry powders. During vapourstabilization, the particles obviously tend to fuse together to someextent, which must be controlled. Adequate care must be paid to preventcontamination of drug during the treatment.

Suspension of an active drug in a volatile solvent in making a powderfor inhalation is mentioned in U.S. Pat. No. 5,503,869. Here onlymicronized drug is suspended in HFA-propellants in order to fix an exactdose on a carrier net of metal, plastic, ceramic or similar material.When the propellant is evaporated, the drug can be blown into the air tobe inhaled. No stabilization of the drug is mentioned.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents the X-ray diffraction (XRD) patterns of three salbutamolsamples.

FIG. 2 presents the X-ray diffraction (XRD) patterns of three samples ofSteroid A.

To overcome the drawbacks of the prior art the present inventionprovides a method for preparing a stable and homogenous dry particulatedproduct which method is characterized in that the particles aresuspended in a suspending agent, and from the thus obtained suspensionthe suspending agent is evaporated.

The other characteristics of the method of this invention are revealedin the claims 2-13.

The invention also concerns the product obtained by the method of thisinvention. The product is stable for longer periods and the particulatematerial is homogenous.

Attempts to manufacture a lactose blend containing only 0.5 percents ofan active drug by dry mixing failed because it was not possible toobtain a totally homogenous mixture of the ingredients by dry-mixing. Itwas found that the formulation always contained some agglomerates of theactive drug, which spoiled the delivered dose uniformly in a reservoirpowder inhaler. However, by mixing the ingredients as a n-hexanesuspension aided by sonic treatment, a totally homogeneous blend wasobtained after evaporation of heptane on a water bath.

When this method was used to make a formulation of salbutamol sulphateand lactose, a homogenous formulation was obtained, but its stabilitywas not satisfactory; the drug particles agglomerated to an unacceptablelevel at room temperature for six months.

One test formulation was left at room temperature as heptane suspensionover the weekend in a glass bottle, followed by evaporation of heptaneon a water bath. Surprisingly, it was found later that this formulationremained stable for over two years at room temperature. Apparently theprolonged suspension state stabilized the formulation probably due tophysical changes in the active substance.

EXAMPLE 1

Tests with Salbutamol Sulphate

Three samples of micronized salbutamol sulphate were stirred 7 hours at50, 60 and 70° C. as n-heptane suspension. Then the solvent wasevaporated in vacuum.

Röntgendiffraction (XRD) studies suggested that a detectable amount ofthe drug was amorphous in the untreated sample but could berecrystallized during the treatment. Seven hours at 60 and 70° C.resulted in practically total crystallinity and slightly less at 50° C.

When a sample of micronized drug was stored 10 hors at 40° C. and 50%relative humidity (RH), a clear decrease took place in the amount ofamorphous matter. XRD patterns of three samples are shown in FIG. 1.

In FIG. 1, the XRD patterns of the three salbutamol samples, which wereeach treated differently before analysis is shown as follows:

1=micronized

2=stored 100 hours at 40° C., 50% RH

3=stirred 7 hours at 70° C. as n-heptane suspension.

Microcalorimetric (IMC) studies verified good stability of the treatedsamples in presence of moisture. The untreated sample was clearlyunstable, especially at a RH of over 50%.

EXAMPLE 2

Preparing a Salbutamol Formulation

Micronized salbutamol sulphate was suspended in n-hexane to a thinslurry, aided by gentle sonic treatment at room temperature. Lactose(325 mesh) was added during mechanical stirring. The suspension wasstirred some hours at 50° C., followed by evaporation of the solvent ina rotating evaporator. A well-flowing powder was the result.

Homogeneity of the drug in the formulation was extremely good, showingRSD values for 2 mg samples of only 1-3%.

Characteristics for this formulation, when used with a model reservoirdevice, are:

Respirable fraction in delivered dose 0.4-0.6 RSD % for delivered doseuniformity < 10 Stability at room circumstances over 2 years  Stabilityat 40° C./75% RH over ½ years

The characteristics are repeatable from batch to batch and the methodhas been scaled up for production.

EXAMPLE 3

Tests with the experimental steroid A

Attempts to make a lactose blend of a n-hexane suspension method at roomtemperature failed because the particle size of the active drug in thedelivered dose increased within weeks to an unacceptable level.

XRD studies suggested large differences in micronized and unmicronizedmaterials, obviously due to different amorphous contents.

Freshly micronized drug showed no sharp diffraction patterns whichindicates very high amorphous content. When stored at room temperaturefor some months, a considerable fraction of the amorphous matter hadbeen recrystallized. Also the initial mean particle size had beenincreased close to the upper acceptable limit.

Samples of some months ago micronized material were suspended inn-heptane and stirred 7 and 16 hours at 70° C., followed by drying. XRD-and IMC-studies confirmed total recrystallization of both samples.

XRD patterns of three samples are shown in FIG. 2.

In FIG. 2, the XRD patterns of three samples of Steroid A, which wereeach treated differently before analysis is shown as follows:

1=micronized

2=stored 100 hours at 40° C., 50% RH

3=stirred 7 hours at 70° C., as n-heptane suspension.

EXAMPLE 4

Preparing a Formulation of Steroid A

The suspension of the drug in n-heptane was stirred 16 hours at 70° C.Than lactose was added during stirring. The solvent was removed byvacuum in a rotatory evaporator. As a result, free flowing dry powderwas obtained. Stability of the formulation was studied in extremeconditions (40° C./75% RH) by metering the small particle fraction inthe delivered dose, when the model reservoir device was used. No changein the particle size distribution or respirable fraction in thedelivered dose could be seen, when tested after 2 and 4 weeks. Theresults indicate superb stability of the formulation compared to earlierattempts with untreated micronized drug.

EXAMPLE 5

Tests with the Experimental Steroid B

Four samples of micronized drug were treated in heptane-ethanol (96:4)and dried:

1. mixing 30 minutes at room temperature

2. mixing 7 hours at room temperature

3. mixing 30 minutes at 50° C.

4. mixing 7 hours at 50° C.

XRD-studies revealed no large differences between the samples. However,the untreated drug showed the lowest peak height which suggests thelargest amorphous content. Specific surface area and the energy formoisture absorption during transfer from 0 to 80% RH were metered:

Area m²/g ΔH J/m² Micronized, untreated 6.55 1.21 Sample 1 6.17 0.95 25.30 0.99 3 5.69 0.94 4 5.38 1.00

The differences are small but indicate that a physical change took placeduring the treatment and the treated samples are in a more stable statecompared to the untreated sample. The overall results encourage to usesuspension stabilization using short treatment at normal or slightlyelevated temperature.

Further experiences and clarifications on the method

Budesonide and three experimental drugs for inhalation have beenformulated using the suspension mixing method. Coarse lactose or glucosewas used as the carrier and the drug-carrier ratios varied between 1:200and 50:100. N-alkane alone or mixed with a small amount of ethanol ormethanol was used as suspending agent. In all cases short mixing timeswere used, followed by removal of the suspending agent in a rotatingevaporator. Budesonide formulation showed excellent homogeneity andstability; no changes in the particle parameters have been found at roomcircumstances within one year.

The formulations of the three experimental drugs showed excellenthomogeneity and acceptable stability.

The suspending method is a very useful method for homogenizing, even ifall of the ingredients were in a stable state. If not stable, it is easyto increase the mixing time and/or mixing temperature and monitor theresults by physical methods instead of timely stability tests. Duringthis stabilization, the essential benefit of the suspension method isthat the liquid prevents agglomeration of the particles duringrecrystalization.

The manufacturing process can be done in a totally closed system inabsence of water. The process is very safe in respect to anycontamination and can be used in large-scale production. The mixingvessel can be equipped with mechanical stirrer, ultrasonic transmitter,heating and filtering means and vacuum evaporation so that theformulation is ready to use after the process.

There seems to be no other limitations concerning the suspending agent,but it must be chemically inert in respect of the formulationcomponents, fairly volatile and the components must be practicallyinsoluble in the suspending agent. N-alkanes are ideal in most cases.Small amounts of methaol, ethanol, acetone, and the like, may be used toimprove wetting of the powders. Even absolute ethanol and halogenatedhydrocarbons, such as CFC 11 and HFC 227, have been used successfully inmaking a salbutamol sulphate—lactose monohydrate formulation.

If heat treatment is used, it can be conducted separately for the drugand the carrier or jointly for the drug, carrier and other possibleingredients concerned. It is preferred to treat both the drug and thecarrier, because also the carrier may contain unstable matter and causeformulation changes during storage. As shown with salbutamol, some hoursmixing in n-hexane at 50° C. will produce a practically stableformulation.

What is claimed is:
 1. A method for preparing a physically stable andhomogenous powdered pharmaceutical preparation to be inhaled comprisingparticles of a pharmaceutical and at least one physiologicallyacceptable additive, said method comprising: suspending particles ofsaid preparation in a suspending agent, thereby forming a suspension,wherein the particles are essentially insoluble in the suspending agent,and; evaporating the suspending agent from the suspension, wherein saidparticles comprise the particles preparation and the carrier inadmixture.
 2. A method according to claim 1, wherein the suspendingagent is selected from the group consisting of: alkanes, alcohols,ketones and mixtures thereof.
 3. A method according to claim 2, whereinthe suspending agent is selected from the group consisting of: analkane, preferably n-hexane or heptane, an alcohol, and a halogenatedhydrocarbon.
 4. A method according to claim 1 wherein the suspendedparticles are deagglomerated and/or homogenized by stirring.
 5. A methodaccording to claim 1, further comprising ultrasonic treatment of thesuspension.
 6. A method according to claim 1, wherein the suspension isstored for a time sufficient to allow contact between the particles andthe suspending agent before evaporation.
 7. A method according to claim1, wherein the suspension is stored for a time between about 3 minutesand 5 days.
 8. A method according to claim 1, wherein said suspending isat a temperature of greater than about room temperature.
 9. A methodaccording to claim 8, wherein said temperature is between about 40° C.and about 90° C.
 10. A method according to claim 1, wherein the activeagent is an organic compound containing an amorphous substance.
 11. Amethod according to claim 10, wherein the active agent is salbutamol.12. A method according to claim 1, wherein the active agent is asteroid.
 13. A method according to claim 1, wherein the active agent isbudesonide.
 14. The product obtained by the method according to claim 1.15. The method according to claim 3, wherein the alkane is selected fromthe group consisting of n-hexane and n-heptane.
 16. The method of claim3, wherein said alcohol is methanol or ethanol.
 17. The method accordingto claim 7, wherein the suspension is stored for about 3 hours.
 18. Themethod according to claim 9, wherein said temperature is between about40° C. and about 70° C.
 19. The method according to claim 9, whereinsaid temperature is between about and 50° C. and about 70° C.